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Male Speaker: The 20th century opened with the rediscovery
of Mendel and ended with the sequencing of the human genome.
By the middle of that century, the structure of DNA was deduced by James Watson and Francis
Crick using the x-ray crystallography images of Rosalind Franklin.
Male Speaker: I just turned over a page in my life and said,
"This is the new book."
Male Speaker: None of these things could be understood until
we knew the structure of DNA.
The characteristic of this discovery is it was so desperately needed.
It was desperately needed.
Anybody who wanted to apply science to understanding life was just marking time, waiting for that
to happen.
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Male Speaker: There one saw immediately how all many of
the questions that had arisen in genetics could be onset and that the model actually
explained how one could get a chemical basis, if you like, for inheritance.
Male Speaker: So that from somebody like Jim and Francis's
standpoint, they could say the critical question in biology was, "How does DNA work?"
And we'll learn about that by looking at its structure.
Male Speaker: The questions had a linear flow to them, and
with Francis there to tell us what they really -- you know, to help formulate them, it was
like a logic game.
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Male Speaker: I was meeting together with Jim and Francis
and Sydney Brenner, who was visiting, and Jim points out the window and says, "See that
fellow down there?
That's Frank Stahl and he thinks he's pretty hot stuff.
Let's give him the Hershey-Chase Blender Experiment to do all by himself in a single afternoon
and see if he could do that."
So I thought, "Oh, this poor guy down there.
I'd better go talk to him."
So I went downstairs and I introduced myself, and here's this fellow, who is actually selling
gin and tonics.
He had a big bottle of gin and tonic and ice and limes, and people would come by and he'd
sell them a gin and tonic and make a few for himself that way.
And he was trying to solve a problem that involved radiation, genetics, and bacteriophage.
And we got to be friends and started talking.
Turned out he was going to Caltech.
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Male Speaker: At that time this would be in the '50s, early
'60s.
Caltech was a major center for the new molecular biology.
Both the work being done there and the fact that everybody was active in the field would
come through Caltech at one time or another and talk.
The famous businessman Stahl experiment was being done at Caltech, where they demonstrated
that the two strands actually do come apart on replication.
Male Speaker: I had an idea, which wasn't the right idea,
but with Frank Stahl, we got to the right idea eventually, for how to test this semi-conservative
replication.
And so the idea of the experiment was to start by growing bacteria in heavy medium.
We used heavy nitrogen, which you could buy in those days -- and still buy.
And then that would give only one band in the place where heavy DNA should go, and then,
quickly separate those bacterial cells from their medium by centrifuging them.
And re-suspend them in light medium, so now any new DNA would be made out of light nitrogen,
and that would form a band higher up in the two, near the top.
Now, if DNA replicates semi-conservatively, that heavy DNA -- both chains are heavy -- if
it comes apart, each two chains separately, and makes a new chain, then you'd have DNA
that has one heavy chain and one light one, and that would be half-heavy.
It would form a band in between the fully heavy and the fully light.
And when everything is replicated once and only once, the band would be exactly in between
and they would be the only thing you would see.
And that's what happened.
Male Speaker: Before Meselson-Stahl's experiment, there
were several competing theories about how DNA replicated itself.
Meselson-Stahl demonstrated decisively that only one of these was right, and this was
the one that had been advanced by Watson and Crick in their original paper in 1953.
The news of Meselson-Stahl traveled very rapidly through the world of molecular biology on
both sides of the Atlantic.
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Male Speaker: It had been known for some time that proteins
were not made in the nucleus but they were made in the cytoplasm, and RNA was involved
in this.
And so people thought that RNA would be involved in the manufacture of proteins once this had
come about.
And so the puzzle was that once we had got to the idea that proteins were made in ribosimes
[sic] -- in ribosomes, sorry -- then the question was where was the information?
How did you get the information out of DNA and get it into ribosomes?
Male Speaker: And out of this came the messenger RNA hypothesis
with Ren Jacob [spelled phonetically] and Brenner and Meselson were involved in putting
that forward.
Male Speaker: And then it was called the messenger because
it took the message from the DNA, see, the message from the DNA into the cytoplasm, where
it was transformed.
Male Speaker: In England, Sydney Brenner, and in France,
François Jacob, were devising a theory about how the information in DNA was carried out
to the cell.
This involved a molecule called RNA, and in 1960, they went to Caltech to use the Meselson-Stahl
methods to see if they were right.
Male Speaker: We arrived there to do this experiment.
Had about three weeks to do it in.
And it didn't work for quite a long time.
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We were centrifuging ribosomes in very strong salt and it didn't occur to us we had to up
the magnesium, because the salt was competing with it and everything came apart.
Very delicate experiment.
Very difficult to do.
And so, once that realization came to me on a beach, we ran back to the lab and, because
I got up and started to jump up and down and say, "It's the magnesium!
It's the magnesium!
Let's go!"
So we did the experiment again.
It was the last time, and we actually found that it worked.
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Male Speaker: The key element in the central dogma was the
adapter -- the tRNA -- another idea of Crick's.
Male Speaker: Gamaroff [spelled phonetically] had created
the coding problem -- formulated the coding problem as one in which he looked at the DNA
and saw various cavities.
And so he very naively assumed some properties about these cavities which were wrong.
Male Speaker: Francis Crick saw that when he suggested the
adapter molecules, RNA, and the messenger concept, which came from Jacob and Brenner
and others.
Male Speaker: The adapter was nucleic acid.
And that you had an enzyme that coupled the amino acid to the adapter.
And then the adapter would go find its place on the nucleic acid and, of course, at the
time he put this forward, a biochemist stood up and said, "This is impossible," on the
grounds that had there had been 20 enzymes, they would already have discovered them.
So there aren't 20.
Male Speaker: And that was the last piece of the puzzle,
because now you had the transfer from DNA, the messenger RNA, the adapters, made into
protein, and then proteins could go out and do their thing.
Male Speaker: But that still left open the question of the
code; that is, how is it that the sequence of base pairs in the DNA actually instructs
the ribosomes in the cell what kind of proteins to produce.
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Male Speaker: Watson and Crick wrote two papers.
The first paper was the structure itself and the second paper was about the implications,
that last sentence of the first paper was.
And in that, it's already clear that we're talking about a code, that we're talking about
ways of decoding.
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Male Speaker: Meanwhile the coding problem sort of bounced
along.
Brenner and Crick did their very ingenious experiment, suggesting that it was probably
a triplet code.
Male Speaker: We needed then to see that we could explain
everything by mapping one sequence written in a four-letter language onto another sequence
written in a 20-letter language.
And that formulated the problem of the genetic code.
Male Speaker: I was aware of ideas about the code, but they
didn't have much meaning to me.
I mean, Crick and Brenner, I remember in 1957, I think, came to the NIH and gave a talk.
I don't even know if they mentioned anything about the code.
I mean, I thought that messenger RNA probably existed and directed amino acid incorporation
into protein.
Male Speaker: d'Arenberg [spelled phonetically] did the
dramatic experiment with the in vitro protein synthesizing systems showing that polyuridylic
acid coded for polyphenylalanine.
Male Speaker: We went ahead and we fractionated ribosomal
RNA, and we found, as we expected, that only a small portion of the ribosomal RNA was active
as a template for protein synthesis.
So then I rounded up as many different kinds of RNAs as I could find, and I got some viral
RNA, tobacco mosaic virus RNA, some yeast ribosomal RNA, and polyU.
Female Speaker: One of the polymers we made was a polymer
with just uridylic acid residues.
And one day, Marshall Nirenberg appeared.
He worked down the hall in another lab, and he appeared at the door and wanted some polyU.
And that was the first opportunity to define one of the codons in DNA.
Male Speaker: PolyU stimulates the incorporation of phenylalanine
into protein.
That was staggering because it was clear that a sequence of Us in polyU corresponded to
the RNA codon for phenylalanine.
Male Speaker: And, of course, the famous polyU, polyuridylic
acid, worked.
It a uniform product of polyphenylalanine, which you could test by incorporation.
And so it became very clear that you could get quite far.
Male Speaker: We call that, ultimately, the genetic code.
And it took about 10 years after the DNA structure for the genetic code itself to be worked out.
Male Speaker: Tom Caskey and Dick Marshall then asked the
question, "Is the code universal?"
And they compared the code of e-coli with transfer RNA from the code of Xenopus and
a hamster -- a mammal.
And they found that it was the same code.
And then when it happened, you had this enormous, rapid development -- getting the code, understanding
mutation, understanding protein synthesis.
It all had to happen, like just a trunk opening up and spilling out.
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